Paths of Progress Spring/Summer 2013

Man on a Mission

Kenneth Anderson, MD (right), has had a lifelong friendship with New England Patriots owner Robert Kraft (left), a passionate supporter of the fight against cancer.

Among the many photographs lining the shelves in his office, Ken Anderson, MD, is quick to point out one. In it, he stands with Robert Kraft, owner of the New England Patriots and patron and co-founder, with Anderson, of the Kraft Family Blood Donor Center at Dana-Farber Cancer Institute and Brigham and Women's Hospital. The two are smiling as Anderson holds up a 2004 Super Bowl ring.

Anderson, who is director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics at Dana-Farber/Brigham and Women's Cancer Center, says he counts Kraft as a "friend for life, both personally and professionally." Anderson, the Kraft Family Professor of Medicine at Harvard Medical School, and Kraft have been close friends for 30 years. Anderson says it's relationships like these – with colleagues and collaborators, trainees, and, most important, with patients and families he has cared for – that are the secret to his success.

In his four decades of practice and research, including 32 years at Dana-Farber, Anderson has played a central role in transforming myeloma, a cancer of the bone marrow, from a near immediate death sentence to, in many cases, a chronic, manageable illness. From the 1970s through the ‘90s, not a single new myeloma drug made it into clinical practice. But during the last decade, Anderson, a slight man with kindly eyes and a ready smile, helped shepherd multiple new drugs from laboratory bench through regulatory approval and to the patient bedside.

"Partnership is absolutely key," says Anderson, who received a 2012 Medal of Honor in Science from the American Cancer Society for bringing his research into the clinic. "We practice team science. We work with industry, regulatory authorities, and funding agencies. But most important, our patients are the heroes, inspiration, and reason for all we do."

Anderson arrived at Johns Hopkins University in 1973 for medical school, inspired by his mother, a nurse, to become a small-town general practitioner. He also had a keen interest in science. In his mind, however, blending science and the practice of medicine as he conceived it – "on the front lines, taking care of people in the community" – wasn't in the realm of possibility.

Then he met Richard Humphrey, a multiple myeloma doctor who was growing myeloma tumor cells in the laboratory and testing them against conventional drugs. Humphrey introduced Anderson to clinical research, and also taught him the meaning of success: Make science count for patients, and treat patients as family.

So imbued is Anderson with these two principles that he has, by word and example, passed them on to those he mentors. "He always told me, as long as you keep the patient in mind, you'll never go wrong," says Noopur Raje, MD, who trained in Anderson's lab a decade ago and now leads her own myeloma lab and practice.

In the early 1970s, there were very few people working on myeloma and survival was measured in months. "There was a glaring and urgent need to make things better for patients," says Anderson.

Research into myeloma was also primed for improvement. Not only are myeloma tumor cells relatively easy to gather from patients, through bone marrow aspirations, they also grow readily in the laboratory, making it possible to model the disease and put science to work against it.

The stage was set. Anderson began pursuing myeloma research immediately.

Making Science Count

Anderson attributes many of his subsequent discoveries to simply following science trends. "In the ‘80s, it was a Golden Age of monoclonal antibodies," he says, his eyes sparkling as he recalls treatment advancements that came from this work. Monoclonal antibodies grab onto invaders such as viruses and cancer cells and allow the immune system to attack.

Anderson used antibodies that target myeloma tumor cells to improve the success of bone marrow transplants when patients self-donate marrow. Even after chemotherapy, such marrow still contains some malignant cells. Anderson found that treating it with antibodies helps clear the tumor cells and delays relapse.

Later, Anderson worked to transform bone marrow transplants into stem cell transplants. The method involves harvesting and reintroducing a patient's own blood stem cells to regenerate the blood and immune system after high-dose chemotherapy. Again, this improved survival.

As science began to uncover the importance of cytokines – proteins that cue cells to grow and influence their behavior – Anderson's research expanded in that direction. This led to a better understanding of the cellular circuitry that drives myeloma.

In the mid-1990s, Anderson discovered that a switch inside myeloma cells, NF-kB, was important to myeloma cell growth and survival, making it a promising drug target. At about the same time, colleagues at Harvard Medical School were working on a new drug, an inhibitor that blocks the proteasome, the cell's garbage collector. That drug, it turned out, worked by inhibiting NF-kB, Anderson's prime target.

Further research in Anderson's lab confirmed the effectiveness of the drug against myeloma. Then, in a phase 1 clinical trial, a myeloma patient had a complete response. All signs of the disease vanished.

Just three years later, in 2003, the FDA approved the drug, called Velcade, which today is standard treatment for newly diagnosed myeloma. "It went from the bench to the bedside very quickly," says Anderson, who with his colleagues won the prestigious Warren Alpert Foundation Prize at Harvard Medical School for this work in 2012.

"The whole concept of benchto- bedside-and-back research was really new," says Faith Davies, MD, who joined Anderson's lab in 1999 for a three-year fellowship. She is now a myeloma investigator at the Institute of Cancer Research in London. "Others may have been doing it, but Ken really drove it."

Around the same time, Anderson was investigating thalidomide, another promising myeloma drug. He modeled not just patient tumor cells but also, as he says, "the neighborhood" of the tumor, including non-cancerous immune and other cells.

The tumor's neighborhood – or "microenvironment" – mattered in myeloma treatment because myeloma cells that adhere to the microenvironment don't respond to conventional chemotherapy drugs.

These more life-like models allowed Anderson to discover that thalidomide and its close cousin lenalidomide (brand name Revlimid) work as immunomodulators, drugs that recruit immune cells to fight cancer. Paul Richardson, MD, his colleague and clinical director of the Lipper Center, led the first human trials, setting the stage for the 2006 approval of lenalidomide to treat myeloma.

Modeling the microenvironment has since proven to be a valuable tool in translational research. "Ken's work has shown that when drugs work in laboratory models of the tumor that include the context of the microenvironment, they tend to work better in patients," says Raje, who, along with Davies, collaborated on these findings.

Myeloma Mixology

Researchers now know that cancer is heterogeneous (many genetic mutations drive a single tumor) and must be treated with combinations of therapies that target different drivers. In some forms, such as testicular cancer and certain types of leukemia and lymphoma, such drug cocktails have led to cures.

So Anderson is looking for synergistic combinations of drugs and therapies for myeloma. Synergy can happen if, for example, one drug undoes the mechanisms that cause resistance to another drug.

He also hopes to personalize treatment by categorizing patients based on the molecular pathways that are driving their cancer, as determined by tumor genomics, and to prescribe combinations of drugs based on those categories. "The more we understand, the more we realize how complicated this disease is," says Anderson, who, along with colleague Nikhil Munshi, MD, is finding that myeloma tumors have many mutations even at the very start of the disease. "Hardly ever will it be enough to use just one targeted agent."

One combination, Velcade, Revlimid and Dexamethasone, shows promise in all patients, with all signs of myeloma vanishing in half. Given these unprecedented results, Munshi, Richardson, and Anderson have launched a trial to test this combination in newly diagnosed myeloma patients. Half of the participants will receive stem cell transplants, testing whether the combination increases transplant success, and vice versa.

"My prediction is that science will inform the design of four- or even five-agent treatment combinations that will markedly improve outcomes and lead to potential cures," he says.

Anderson's influence is behind much of the progress made in myeloma over the past four decades. Yet Anderson deftly passes the credit. "I have been blessed to have colleagues here and around the world passionately committed to curing myeloma, and courageous patients who are a daily source of inspiration."

"He's so humble about his achievements," says Raje, who still attends Anderson's weekly lab meetings and calls him regularly for input.

When Anderson looks back on his 40-year journey, he shakes his head in disbelief. "What a privilege it has been for me to watch the natural history of myeloma change, see trainees become leaders, and watch patients share the joys of life with their families. It doesn't get any better than this!," he says. Nevertheless, when he looks ahead, he has the energy of a man just about to begin.